The heart is a muscular pump whose mechanical activation is controlled by electrical stimulation generated at a right atrium and passed to the entire heart. In a normal heart, the electrical stimulation that drives the heart originates as action potentials in a group of pacemaker cells lying in a sino-atrial (SA) node in the right atrium. These action potentials then spread rapidly to both right and left atria. When the action potential reaches an unactivated muscle cell, the cell depolarizes (thereby continuing the spread of the action potential) and contracts. The action potentials then enter the heart's conduction system and, after a short delay, spread through the left and right ventricles of the heart. It should be appreciated that activation signals are propagated within the heart by sequentially activating connected muscle fibers. Each cardiac muscle cell generates a new action potential for stimulating the next cell, after a short delay and in response to the activation signal which reaches it. Regular electrical currents can be conducted in the heart, using the electrolytic properties of the body fluids, however, due the relatively large resistance of the heart muscle, this conduction cannot be used to transmit the activation signal.
In a muscle cell of a cardiac ventricle, the resting potential across its cellular membrane is approximately −90 mV (millivolts) (the inside is negatively charged with respect to the outside). FIG. 1A shows a transmembrane action potential of a ventricle cardiac muscle cell during the cardiac cycle. When an activation signal reaches one end of the cell, a depolarization wave rapidly advances along the cellular membrane until the entire membrane is depolarized, usually to approximately +20 mV (23). Complete depolarization of the cell membrane occurs in a very short time, about a few millisecond. The cell then rapidly (not as rapid as the depolarization) depolarizes by about 10 mV. After the rapid depolarization, the cell slowly repolarizes by about 20 mV over a period of approximately 200 to 300 msec (milliseconds), called the plateau (25 in FIG. 1A). It is during the plateau that the muscle contraction occurs. At the end of the plateau, the cell rapidly repolarizes (27 in FIG. 1A) back to its resting potential (21 in FIG. 1A). Different cardiac muscle cells have different electrical characteristics, in particular, cells in an SA node do not have a substantial plateau and do not reach as low a resting potential as ventricular cells.
In the following discussion, it should be appreciated that the exact mechanisms which govern action potentials and ionic pumps and channels are only partly known. Many theories exist and the field in is a constant state of flux.
The electrical activity mirrors chemical activity in a cell. Before depolarization (at resting), the concentration of sodium ions inside the cell is about one tenth the concentration in the interstitial fluid outside the cell. Potassium ions are about thirty-five times more concentrated inside the cell than outside. Calcium ions are over ten thousand times more concentrated outside the cell than inside the cell. These concentration differentials are maintained by the selective permeability of the membrane to different ions and by ionic pumps in the membrane of the cell which continuously pump sodium and calcium ions out and potassium ions in. One result of the concentration differences between the cell and the external environment is a large negative potential inside the cell, about 90 mV as indicated above.
When a portion of the cell membrane is depolarized, such as by an action potential, the depolarization wave spreads along the membrane. This wave causes a plurality of voltage-gated sodium channels to open. An influx of sodium through these channels rapidly changes the potential of the membrane from negative to positive (23 in FIG. 1A). Once the voltage becomes less negative, these channels begin to close, and do not open until the cell is again depolarized. It should be noted that the sodium channels must be at a negative voltage of at least a particular value in order to be primed for reopening. Thus, these channels cannot be opened by an activation potential before the cell has sufficiently repolarized. In most cells, the sodium channels usually close more gradually than they open. After the rapid depolarization, the membrane starts a fast repolarization process. The mechanism for the fast repolarization is not fully understood, although closing of the sodium channels appears to be an important factor. Following a short phase of rapid repolarization, a relatively long period (200 to 300 msec) of slow repolarization term the plateau stage (25 in FIG. 1A) occurs. During the plateau it is not believed to be possible to initiate another action potential in the cell, because the sodium channels are inactivated.
Two mechanisms appear to be largely responsible for the long duration of the plateau, an inward current of calcium ions and an outward current of potassium ions. Both currents flow with their concentration gradients, across the membrane. The net result is that the two types of current electrically subtract from each other. In general, the flow of potassium and calcium is many times slower than the flow of the sodium, which is the reason why the plateau lasts so long. According to some theories, the potassium channels may also open as a result of the action potential, however, the probability of a potassium channel opening is dependent on the potential. Thus, many channels open only after the depolarization of the cell is under way, or completed. Possibly, at least some of the potassium channels are activated by the calcium ions. In addition, some of the potassium channels are triggered by the repolarization of the membrane. The membrane permeability to potassium gradually increases, following its drop during the rapid depolarization (23 in FIG. 1A). The calcium channels also conduct sodium back into the cell, which helps extend the plateau duration.
The inward calcium current during the normal cardiac action potential contributes to the action potential plateau and is also involved in the contractions (directly and/or indirectly) in the cardiac muscle cells. In a process termed calcium induced calcium release, the inward current of calcium induces the release of calcium ions stored in intracellular calcium stores (probably the sacroplasmic reticulum). The existence and importance of a physical link between the reticulum and the calcium channels in cardiac muscle is unclear. However, the response curve of these calcium stores may be bell-shaped, so that too great an influx of calcium may reduce the amount of available calcium relative to amount made available by a smaller influx.
In single cells and in groups of cells, time is required for cells to recover partial and full excitability during the repolarization process. While the cell is repolarizing (25, 27 in FIG. 1A), it enters a state of hyper polarization, during which the cell cannot be stimulated again to fire a new action potential. This state is called the refractory period. The refractory period is divided into two parts. During an absolute refractory period, the cell cannot be re-excited by an outside stimulus, regardless of the voltage level of the stimulus. During a relative refractory period, a much larger than usual stimulus signal is required to cause the cell to fire a new action potential. The refractory state is probably caused by the sodium channels requiring priming by a negative voltage, so the cell membrane cannot depolarize by flow of sodium ions until it is sufficiently repolarized. Once the cell returns to its resting potential (21 in FIG. 1A), the cell may be depolarized again.
In an experimental methodology called voltage clamping, an electrical potential is maintained across at least a portion of a cell membrane to study the effects of voltage on ionic channels, ionic pumps and on the reactivity of the cell.
It is known that by applying a positive potential across the membrane, a cell may be made more sensitive to a depolarization signal. Some cells in the heart, such as the cells in the SA node (the natural pacemaker of the heart) have a resting potential of about −55 mV. As a result, their voltage-gated sodium channels are permanently inactivated and the depolarization stage (23 in FIG. 1A) is slower than in ventricular cells (in general, the action potential of an SA node cell is different from that shown in FIG. 1A). However, cells in the SA node have a built-in leakage current, which causes a self-depolarization of the cell on a periodic basis. In general it appears that when the potential of a cell stay below about −60 mV for a few msec, the voltage-gated sodium channels are blocked. Applying a negative potential across its membrane make a cell less sensitive to depolarization and also hyperpolarizes the cell membrane, which seems to reduce conduction velocity.
In modern cardiology, many parameters of the heart's activation can be controlled. Pharmaceuticals can be used to control the conduction velocity, excitability, contractility and duration of the refractory periods in the heart. These pharmaceuticals may be used to treat arrhythmias and prevent fibrillations. A special kind of control can be achieved using a pacemaker. A pacemaker is an electronic device which is typically implanted to replace the heart's electrical excitation system or to bypass a blocked portion of the conduction system. In some types of pacemaker implantation, portions of the heart's conduction system, for example an atrial-ventricle (AV) node, must be ablated in order for the pacemaker to operate correctly.
Another type of cardiac electronic device is a defibrillator. As an end result of many diseases, the heart may become more susceptible to fibrillation, in which the activation of the heart is substantially random. A defibrillator senses this randomness and resets the heart by applying a high voltage impulse(s) to the heart.
Pharmaceuticals are generally limited in their effectiveness in that they affect both healthy and diseased segments of the heart, usually, with a relatively low precision. Electronic pacemakers, are further limited in that they are invasive, generally require destruction of heart tissue and are not usually optimal in their effects. Defibrillators have substantially only one limitation. The act of defibrillation is very painful to the patient and traumatic to the heart.
An article entitled “Electrical stimulation of cardiac myoctes,” by Ravi Ranjan and Nitish V. Thakor, in Annals of Biomedical Engineering, Vol. 23, pp. 812 821, published by the Biomedical Engineering Society, 1995, the disclosure of which is incorporated herein by reference, describes several experiments in applying electric fields to cardiac muscle cells. These experiments were performed to test theories relating to electrical defibrillation, where each cell is exposed to different strengths and different relative orientations of electric fields. One result of these experiments was the discovery that if a defibrillation shock is applied during repolarization, the repolarization time is extended. In addition, it was reported that cells have a preferred polarization. Cardiac muscle cells tend to be more irregular at one end of the cell than at the other end of the cell. It is theorized in the article, that local “hot spots” of high electrical fields are generated at the irregular end sites and that these “hot spots” are the sites of initial depolarization within the cell, since it is at these sites that the threshold for depolarization is first reached. This theory also explains that cells are more sensitive to electric fields in their longitudinal direction than in their transverse direction, since the irregularities are concentrated at the cell ends. In addition, the asymmetric irregularity of the cells may explain results which showed a preferred polarity of the applied electric field.
The electrical activation of skeletal muscle cells is similar to that of cardiac cells, in that a depolarization event induces contraction of muscle fibers. However, skeletal muscle is divided into isolated muscle bundles, each of which is individually innervated by action potential generating nerve cells. Thus, the effect of an action potential in skeletal muscle is local, while in a cardiac muscle (where all the muscle cells are electrically connected), an action potential is transmitted to the entire heart from a single location of action potential generation. In addition, the chemical aspects of activation of skeletal muscle is somewhat different from those of cardiac muscle.
An article entitled “Muscle recruitment with infrafascicular electrodes”, by Nicola Nannini and Kenneth Horch, IEEE Transactions on Biomedical Engineering, Vol. 38, No. 8, pp. 769-776, August 1991, the disclosure of which is incorporated herein by reference, describes a method of varying the contractile force of skeletal muscles, by “recruiting” a varying number of muscle fibers. During the recruiting, the contractile force of a muscle is determined by the number of muscle fibers which are activated by a stimulus.
However, it is generally accepted that cardiac muscle fibers function as a syncytium such that each and every cell contracts at each beat. Thus, there are no cardiac muscles fibers available for recruitment (described in an article entitled “Excitation contraction coupling and cardiac contractile force”, by Donald M. Bers, Chapter 2, page 17, Kluwer Academic, 1991, the disclosure of which is incorporated herein by reference). This citation also states that in cardiac muscle cells, contractile force is varied in large part by changes in peak calcium.
An article entitled “Effect of field stimulation on cellular repolarization in rabbit myocardium”, by Stephen B. Knisley, William M. Smith and Raymond E. Ideker, Circulation Research, Vol. 70, No. 4, pp. 707 715, April 1992, the disclosure of which is incorporated herein by reference, describes the effect of an electrical field on rabbit myocardium. In particular, this article describes prolongation of an action potential as a result of a defibrillation shock and ways by which this effect can cause defibrillation to fail. One hypothesis is that defibrillation affects cardiac cells by exciting certain cells which are relatively less refractory than others and causes the excited cells to generate a new action potential, effectively increasing the depolarization time.
An article entitled “Optical recording in the rabbit heart show that defibrillation strength shocks prolong the duration of depolarization and the refractory period”, by Stephen M. Dillon, Circulation Research, Vol. 69, No. 3, pp. 842 856, September, 1991, the disclosure of which is incorporated herein by reference, explains the effect of prolonged repolarization as caused by the generation of a new action potential in what was thought to be refractory tissue as a result of the defibrillation shock. This article also proves experimentally that such an electric shock does not damage the cardiac muscle tissue and that the effect of a second action potential is not due to recruitment of previously unactivated muscle fibers. It is hypothesized in this article that the shocks hyperpolarize portions of the cellular membrane and thus reactivate the sodium channels. In the experiments described in this article, the activity of calcium channels is blocked by the application of methoxy-veraparmil.
An article entitled “Electrical resistances of interstitial and microvascular space as determinants of the extracellular electrical field and velocity of propagation in ventricular myocardium”, by Johannes Fleischhauer, Lilly Lehmann and Andre G. Kleber, Circulation, Vol. 92, No. 3, pp. 587 594, Aug. 1, 1995, the disclosure of which is incorporated herein by reference, describes electrical conduction characteristics of cardiac muscle.
An article entitled “Inhomogeneity of cellular activation time and Vmax in normal myocardial tissue under electrical field stimulation”, by Akihiko Taniguchi, Junji Toyama, Itsuo Kodama, Takafumi Anno, Masaki Shirakawa and Shiro Usui, American Journal of Physiology, Vol. 267 (Heart Circulation Physiology, Vol. 36), pp. H694-H705, 1994, the disclosure of which is incorporated herein by reference, describes various interactions between electro-tonic currents and action potential upstrokes.
An article entitled “Effect of light on calcium transport in bull sperm cells”, by R. Lubart, H. Friedmann, T. Levinshal, R. Lavie and H. Breitbart, Journal of Photochemical Photobiology B, Vol. 14, No. 4, pp. 337 341, Sep. 12, 1992, the disclosure of which is incorporated herein by reference, describes an effect of light on bull sperm cells, in which laser light increases the calcium transport in these cells. It is also known that low level laser light affects calcium transport in other types of cells, for example as described in U.S. Pat. No. 5,464,436, the disclosure of which is incorporated herein by reference.
The ability of electromagnetic radiation to affect calcium transport in cardiac myocytes is well documented. Loginov V A, “Accumulation of calcium ions in myocardial sarcoplasmic reticulum of restrained rats exposed to the pulsed electromagnetic field”, in Aviakosm Ekolog Med, Vol. 26, No. 2, pp. 49 51, March April, 1992, the disclosure of which is incorporated herein by reference, describes an experiment in which rats were exposed to a 1 Hz field of between 6 and 24 mTesla. After one month, a reduction of 33 percent in the velocity of calcium accumulation was observed. After a second month, the accumulation velocity was back to normal, probably due to an adaptation mechanism.
Schwartz J L, House D E, and Mealing G A, in “Exposure of frog hearts to CW or amplitude-modulated VHF fields: Selective efflux of calcium ions at 16 Hz”, Bioelectromagnetics, Vol. 11, No. 4, pp. 349 358, 1990, the disclosure of which is incorporated herein by reference, describe an experiment in which the efflux of calcium ions in isolated frog hearts was increased by between 18 and 21% by the application of a 16 Hz modulated VHF electromagnetic field.
Lindstrom E, Lindstrom P, Berglund A, Lundgren E, and Mild K H, in “Intracellular calcium oscillations in a T-cell line after exposure to extremely-low-frequency magnetic fields with variable frequencies and flux densities”, Bioelectromagnetics, Vol. 16, No. 1, pp. 41 47, 1995, the disclosure of which is incorporated herein by reference, describe an experiment in which magnetic fields, at frequency between 5 and 100 Hz (Peak at 50 Hz) and with intensities of between 0.04 and 0.15 mTesla affected calcium ion transport in T-cells.
Loginov V A, Gorbatenkova N V, and Klimovitskii Vla, in “Effects of an impulse electromagnetic field on calcium ion accumulation in the sarcoplasmatic reticulum of the rat myocardium”, Kosm Biol Aviakosm Med, Vol. 25, No. 5, pp. 51 53, September October, 1991, the disclosure of which is incorporated herein by reference, describe an experiment in which a 100 minute exposure to a 1 msec impulse, 10 Hz frequency and 1-10 mTesla field produced a 70% inhibition of calcium transfer across the sarcoplasmic reticulum. The effect is hypothesized to be associated with direct inhibition of Ca-ATPase.
It should be noted that some researchers claim that low frequency magnetic fields do not have the above reported effects. For example, Coulton L A and Barker A T, in an article entitled “Magnetic fields and intracellular calcium: effects on lymphocytes exposed to conditions for Cyclotron Resonance”, Phys Med Biol, Vol. 38, No. 3, pp. 347 360, March, 1993, the disclosure of which is incorporated herein by references, exposed lymphocytes to radiation at 16 and 50 Hz, for a duration of 60 minutes and failed to detect any changes in calcium concentration.
Pumir A, Plaza F, and Krinsky Vl, in an article entitled “Control of rotating waves in cardiac muscle: Analysis of the effect of electric fields”, Proc R Soc Lond B Biol Sci, Vol. 257, No. 1349, pp. 129 34, Aug. 22, 1994, the disclosure of which is incorporated herein by reference, describe that an application of an external electric field to cardiac muscle affects conduction velocity by a few percent. This effect is due to the hyperpolarization of one end of muscle cells and a depolarization of the other end of the cell. In particular, an externally applied electric field favors propagation antiparallel to it. It is suggested in the article to use this effect on conduction velocity to treat arrhythmias by urging rotating waves, which are the precursors to arrhythmias, to drift sideways to non-excitable tissue and die.
An article entitled “Control of muscle contractile force through indirect high-frequency stimulation”, by M. Sblomonow, E. Eldred, J. Lyman, and J. Foster, American Journal of Physical Medicine, Vol. 62, No. 2, pp. 71 82, April 1983, the disclosure of which is incorporated herein by reference, describes a method of controlling skeletal muscle contraction by varying various parameters of a 500 Hz pulse of electrical stimulation to the muscle.
A reference entitled “Biomedical engineering handbook”, ed. Joseph D. Bronzino, chapter 82.4, page 1288, IEEE press/CRC press, 1995, which is incorporated herein by reference, describes the use of precisely timed subthreshold stimuli, simultaneous stimulation at multiple sites and pacing with elevated energies at the site of a tachycardia foci, to prevent tachycardia However, none of these methods had proven practical at the time the book was written. In addition a biphasic defibrillation scheme is described and it is theorized that biphasic defibrillation schemes are more effective by virtue of a larger voltage change when the phase changes or by the biphasic waveform causing hyperpolarization of tissue and reactivation of sodium channels.
An article entitled “Subthreshold conditioning stimuli prolong human ventricular refractoriness”, Windle J R, Miles W M, Zipes D P, and Prystowsky E N, American Journal of Cardiology, Vol. 57, No. 6, pp. 381 386, February, 1986, the disclosure of which is incorporated herein by reference, describes a study in which subthreshold stimuli were applied before a premature stimulus and effectively blocked the premature stimulus from having a pro-arrhythmic effect by a mechanism of increasing the refractory period of right ventricular heart tissue.
An article entitled “Ultrarapid subthreshold stimulation for termination of atrioventricular node reentrant tachycardia”, Fromer M, and Shenasa M, Journal of the American Collage of Cardiology, Vol. 20, No. 4, pp. 879 883, October, 1992, the disclosure of which is incorporated herein by reference, describes a study in which trains of subthreshold stimuli were applied asynchronously to an area near a reentry circuit and thereby terminated the arrhythmia. Subthreshold stimuli were described as having both an inhibitory and a facilitating effect on conduction. In addition, subthreshold stimuli are described as reducing the threshold of excitability, possibly even causing an action potential.
An article entitled “Inhibition of premature ventricular extrastimuli by subthreshold conditioning stimuli”, Skale B, Kallok M J, Prystowsky E N, Gill R M, and Zipes D P, Journal of the American Collage of Cardiology, Vol. 6, No. 1, pp. 133 140, July, 1985, the disclosure of which is incorporated herein by reference, describes an animal study in which a train of 1 msec duration pulses were applied to a ventricle 2 msec before a premature stimuli, inhibited the response to the premature stimuli, with a high frequency train delaying the response for a much longer amount of time (152 msec) than a single pulse (20 msec). The delay between the pacing of the ventricle and the pulse train was 75 msec. However, the subthreshold stimuli only had this effect when delivered to the same site as the premature stimulus. It is suggested to use a subthreshold stimuli in to prevent or terminate tachycardias, however, it is noted that this suggestion is restrained by the spatial limitation of the technique.
An article entitled “The phase of supernormal excitation in relation to the strength of subthreshold stimuli”, Yokoyama M, Japanese Heart Journal, Vol. 17, No. 3, pp. 35 325, May, 1976, the disclosure of which is incorporated herein by reference, describes the effect of varying the amplitude of a subthreshold stimuli on supernormal excitation. When the amplitude of the stimuli was increased, the supernormal excitation phase increased in length.
In certain heart diseases, either congenital or acquired, natural pacing is replaced or assisted by artificial pacing induced by a pacemaker, which is generally implanted in the patient's chest. Pacemakers known in the art provide artificial excitatory pulses to the heart tissue to control the heart rhythm. Early pacemakers were asynchronous pulse generators that operated at a fixed invariant rate. Later, demand type pacemakers were developed, in which stimulation pulses are produced only when a naturally-occurring heartbeat is not detected within some maximum type period.
Cardiac pacemakers are required to deliver a stimulus pulse of sufficient magnitude and duration to cause an action potential to propagate from the point of excitation, leading to heart muscle contraction. Thus, the primary function of a pacemaker is to regulate heart rhythm rather than the contractility of the muscle. Furthermore, it is known in the art that the use of a pacemaker generally results in decreased contractility of the cardiac muscle and, consequently, a decreased cardiac output (CO) for a given heart rate.
The hemodynamic effect of different types of pacemakers has long been researched. For example, Wessale et al., in an article entitled “Stroke Volume and Three Phase Cardiac Output Rate Relationship with Ventricular Pacing,” Pacing Clin Electophysiol 13 (May, 1990), pp. 673-680, describe a three-phase relationship between pacing rate and cardiac output. At a low pacing rate CO increases with increasing rate. There is an intermediate range of rates in which CO stays steady, and above which a further rate increase will cause a decrease in CO. This, of course, causes a major problem for the patient, since a demand for a higher pacing rate typically stems from a demand for an increase in tissue oxygen supply. Research and clinical experience show that with various types of pacemakers, some cardiac output augmentation may take place initially, but is not maintained on a long-term basis and may even deteriorate compared to the situation before beginning pacing. (See, for example, Wirtzfeld et al., “Physiological Pacing: Present Status and Future Developments,” Pacing Clin Electrophysiol 10 (January, 1987), pp. 41-47.
Talit et al., in “The Effect of External Cardiac Pacing on Stroke Volume,” Pacing Clin Electophysiol 13 (May, 1990), pp. 598-602, evaluated the hemodynamic effects of external cardiac pacing on ten subjects and found a decrease of 23% in stroke volume and 14% decrease in cardiac output when compared to the values of these parameters that were obtained prior to pacing.
It is a principle of pacing that the optimal pacing mode is that which gives optimal hemodynamics, thus making the patient the most comfortable. This principle has guided researchers to attempt to regulate the mechanical performance of the heart by synchronization of the contraction of the heart chambers using sequential A/V or multisite pacing. Attempts have also been made to provide pacemakers with improved physiological sensing capabilities, for use in giving feedback to the pacemaker.
FIG. 24A is a schematic diagram illustrating elements of a pacemaker pulse generator 1020 for pacing a heart 1022, as is known in the art. Such pacemakers are described, for example, in Design of Cardiac Pacemakers, John G. Webster, ed. (IEEE Press, Piscataway, N.J., 1995), which is incorporated herein by reference. Pacemaker 1020 comprises a battery 1024 or other power source, which charges a tank capacitor 1028 via a charge pump 1026 (or voltage multiplier). To apply a pacing pulse to heart 1022, a switch 1030 is closed, transferring stored charge from capacitor 1028 via a DC-blocking capacitor 1034 to electrodes 1036. Switch 1030 is then opened, and a discharge switch 1032 is preferably closed in order to remove charge buildup on capacitor 1028.
FIG. 24B is a timing diagram illustrating a typical pacing signal 1038 generated by pacemaker 1020 across electrodes 1036. Switch 1030 is closed for a very short period, typically between 0.1 and 1.5 ms, in order to produce a sharp, narrow, cathodic (negative voltage) pacing pulse 1040 with a total discharge of 0.1-50 μC. The amplitude and duration of the pulse are programmable in order to adjust the stimulus that is applied to the heart. Typically, for safety and reliability of pacing, the amplitude of the pulse is set empirically to roughly twice the rheobase, which is the minimum electrical current that will cause the myocardial cell membranes to depolarize. The pacing pulse duration is set to up to twice the chronaxie time, which is the pulse duration that will cause depolarization at twice the rheobase current. A longer duration or higher amplitude has been considered undesirable, because it would tend to discharge battery 1024 prematurely without any improvement in the pacemaker performance or in the physiological performance of the heart or the safety of the pacing. In fact, substantial research and product development efforts in the pacing field have been dedicated to finding pacing methods and waveforms that reduce the amount of energy that must be applied to the heart, in order to prolong battery and circuit lifetime.
After pacing switch 1030 is opened, discharge switch 1032 is closed, typically for about 20 ms, causing an anodic (positive voltage) discharge phase 1042 to appear across electrodes 1036. The specific duration and amplitude of this phase of the pacing waveform are not significant from the point of view of pacing, since it is intended only to remove residual charge and does not provide any stimulation to the heart.
A number of authors have suggested varying the shape and/or duration of the pacing pulse in order to obtain improved pacing effects or to reduce the pulse amplitude or charge flux needed to provide a desired level of stimulation. Among other techniques, biphasic pulses (including both cathodic and anodic portions) or bursts of pulses have been used for defibrillation and antitachycardic pacing.
For example, U.S. Pat. No. 5,531,764 to Adams et al. describes an implantable defibrillator having programmable shock waveforms of different shapes and magnitudes in different combinations and sequences.
Fain et al., in their work “Improved Internal Defibrillation Efficacy with a Biphasic Waveform,” in the American Heart Journal 117 (February, 1989), pp. 358-64, show that a biphasic truncated exponential shock waveform significantly reduces the initial voltage and energy requirements for effective defibrillation.
Fromer et al., in an article entitled “Ultrarapid Subthreshold Stimulation for Termination of Atrioventricular Node Reentrant Tachycardia,” in Journal of the American College of Cardiology 20 (October, 1992), pp. 879-83, describe the application of a train of stimuli to intracardiac electrodes in order to terminate tachycardic episodes without the need for cardioversion. The train ranged from 4 to 16 pulses, each 2 ms long. The pulse train was thus meant, under certain circumstances, to take the place of or precede more drastic defibrillative measures, and not to pace the heart.
Similarly, Hedberg, et al., in U.S. Pat. No. 5,622,687, describe an implantable defibrillator which applies a train of low-energy defibrillation pulses in order to defibrillate the heart with a lower total energy flux than would ordinarily be required using conventional defibrillation pulses. The train includes between 2 and 10 pulses, preferably about 10 ms apart. The width of the pulses is not specified. The pulses may be either monophasic or biphasic. In any case, the clinical and technical considerations in generating signals of the type employed by a defibrillator are entirely different from those involved in pacing the heart.
Kinsley, et al., in an article entitled “Prolongation and Shortening of Action Potentials by Electrical Shocks in Frog Ventricular Muscle,” in the American Journal of Physiology 6 (Heart Circ. Physiol. 35, 1994), pp. H2348-H2358, describe measurements of contraction length and intracellular action potential following application of shocks to heart tissue. By varying the strength of the shocks, the contraction strength of the tissue could be increased, and the action potentials lengthened or shortened. The authors propose that such techniques could be used in defibrillation, but make no suggestion with regard to pacing the heart.
U.S. Pat. No. 4,312,354, to Walters, describes a pacemaker with a circuit for pulse width modulation of the stimulus pulses applied to the heart. The purpose of the modulation is not to directly affect the pacing itself, but rather to afford a means for indicating to an external telemetry unit a control state of the pacemaker.
Thakor, et al., in an article entitled “Effect of Varying Pacing Waveform Shapes on Propagation and Hemodynamics in the Rabbit Heart,” in The American Journal of Cardiology 79 (Mar. 20, 1997), pp. 36-43, describe experiments using biphasic pacing pulses to increase the speed of electrical conduction in heart muscle fibers. Both monophasic and biphasic pulses of 2 to 8 ms total duration were applied to isolated muscle fibers using unipolar electrodes. The biphasic pulses consisted of a single cathodic pulse immediately followed by a single anodic pulse, or vice versa. The article reports that propagation of the resulting electrical potentials along the fibers was significantly faster for the biphasic stimulation. It was observed that pacing with an anodic/cathodic biphasic pulse resulted in faster electrical conduction, and led to an earlier development of pressure in the muscle fiber and a shorter duration of the pressure waveform than did monophasic pulses. The authors suggest that the biphasic pulse could be associated with the ability to augment muscular contraction.
PCT patent application PCT/IL97/00012, published as WO 97/25098, to Ben-Haim et al., which is incorporated herein by reference, describes methods for modifying the force of contraction of at least a portion of a heart chamber by applying a non-excitatory electric field to the heart at a delay after electrical activation of the portion. The non-excitatory field is such as does not induce activation potentials in cardiac muscle cells, but rather modifies the cells' response to the activation. The non-excitatory field may be applied in combination with a pacemaker or defibrillator, which applies an excitatory signal (i.e., pacing or defibrillation pulses) to the heart muscle.
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